tbuckley/cabot-search huggingface dataset:
Abstract C054: Hypoxia promotes a durable epithelial-mesenchymal transition in pancreas cancer through a histone methylation-MAPK signaling axis
Authors: Brooke A. Brown, Paul J. Myers, Sara J. Adair, Jason R. Pitarresi, Shiv Sah Teli, Peppi Karppinen, Ben Z. Stanger, Todd W. Bauer, Matthew J. Lazzara
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) tumors are poorly vascularized and exhibit regions of hypoxia. Here, we demonstrate that this feature of the tumor microenvironment promotes epithelial-mesenchymal transition (EMT), which occurs early in PDAC and drives chemoresistance, and we identify the underlying signaling mechanism. Analysis of publicly-available human transcriptomics and proteomics demonstrated that PDAC cells or tumors enriched in mesenchymal markers were also enriched in markers of hypoxia or HIF activity. Furthermore, in lineage-traced autochthonous, orthotopic patient-derived xenograft, and orthotopic or subcutaneous implanted cell line models of PDAC, hypoxic tumor tissue regions were enriched for neoplastic cells that had undergone EMT. In cell culture experiments, PDAC cells from human and mouse tumors exhibited an ability to undergo EMT in response to 1% O2, with loss of membranous E-cadherin, increased vimentin protein expression, and transcriptional changes indicative of both hypoxia and EMT. Moreover, EMT in response to hypoxia was substantially more persistent than that observed in response to growth factors, and a hypoxia fate mapping system revealed that once-hypoxic cells could retain mesenchymal characteristics outside hypoxic tumor regions. To understand the mechanism for EMT in response to low oxygen tension, we constructed a multivariable linear regression model of the dependence of the hypoxic gene signature on different gene sets in PDAC ductal cells, which identified MAPK signaling as the most important feature. Consistent with the model inference, in both in vitro and in vivo settings, hypoxic cells showing evidence of EMT displayed elevated MAPK signaling. We further demonstrated that MAPK activation in hypoxia was potentiated by suppressed activity of a histone demethylase and concomitant loss of protein phosphatase expression, which reinforced the mechanism by stabilizing the expression of a histone methyltransferase. Thus, this study identifies a tumor microenvironment-initiated mechanism leading to EMT and nominates several potential drug targets whose antagonism may promote PDAC chemoresponse. Citation Format: Brooke A. Brown, Paul J. Myers, Sara J. Adair, Jason R. Pitarresi, Shiv Sah Teli, Peppi Karppinen, Ben Z. Stanger, Todd W. Bauer, Matthew J. Lazzara. Hypoxia promotes a durable epithelial-mesenchymal transition in pancreas cancer through a histone methylation-MAPK signaling axis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C054.
Abstract C050: Elucidating mechanisms of endocrine-exocrine signaling in obesity-driven pancreatic cancer
Authors: Cathy C. Garcia, Lauren Lawres, Sherry Agabiti, Jaffarguriqbal Singh, Alex Tong, Aarthi Venkat, Daniel B. Burkhardt, Rebecca Cardone, Richard G. Kibbey, Smita Krishnaswamy, Mandar D. Muzumdar
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Various epidemiologic studies have shown that obesity increases the risk of PDAC. With rising rates of obesity worldwide, it is imperative that we understand the mechanisms by which obesity promotes PDAC progression. Therefore, to study the effect of obesity on PDAC, we combined a well-established genetic model of obesity (Lepob/ob) with a faithful oncogenic Kras-driven pancreatic cancer model (KC: Pdx1-Cre; KrasLSL-G12D/+) and showed that obese mice had both increased tumor burden and shortened survival compared to their lean counterparts. Strikingly, weight loss (via AAV-leptin rescue or caloric restriction), decreased tumor development, demonstrating that the tumor-promoting effects of obesity can be reversed. Bulk-RNA sequencing of tumors from obese mice exhibited aberrant expression of islet beta-cell genes, including those coding for the peptide hormones cholecystokinin (CCK) and amylin (Iapp). Single-cell RNA sequencing of islet beta-cells from wild-type, high fat diet-fed, and Lepob/ob mice revealed a trajectory of beta-cell adaptation to obesity with dysregulated hormone expression, including downregulation of insulin expression and upregulation of CCK and Iapp, concordant with loss of beta-cell identity transcription factors and beta-cell dysfunction. In silico analyses using dynamic optimal transport (TrajectoryNet) demonstrate that CCK-expressing beta-cells arise from pre-existing insulin low-expressing beta-cells, arguing for baseline beta-cell heterogeneity as a determinant of aberrant hormone expression. Lastly, transgenic expression of CCK or Iapp in beta-cells was sufficient to promote oncogenic Kras-driven pancreatic tumorigenesis, while converse beta-cell ablation impeded tumor progression in mice. Together, these results uncover a novel mechanism of obesity driven PDAC by local hormonal signaling between endocrine islets and exocrine acinar cells and reveal pancreatic endocrine adaptations that could be targeted to halt exocrine tumorigenesis. Citation Format: Cathy C. Garcia, Lauren Lawres, Sherry Agabiti, Jaffarguriqbal Singh, Alex Tong, Aarthi Venkat, Daniel B. Burkhardt, Rebecca Cardone, Richard G. Kibbey, Smita Krishnaswamy, Mandar D. Muzumdar. Elucidating mechanisms of endocrine-exocrine signaling in obesity-driven pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C050.
Abstract PR003: Race plays a role on the rate of transdifferentiation in human pancreatic acinar ductal metaplasia and its' drug response
Authors: Corey Perkins, Jinmai Jiang, Hesam Hakimjavadi, David Quashie, Yating Mao, Jamel Ali, Thomas D. Schmittgen
Journal: Cancer Research (2022)

Abstract Pancreatic diseases (acute/chronic pancreatitis, type 2 diabetes, pancreatic cancer) disproportionately affect the Black/African American community in comparison to non-White Hispanics and Whites. Acinar to ductal metaplasia (ADM), the process by which pancreatic acinar cells transdifferentiate into ductal epithelial cells, is believed to be an initiating event of pancreatic ductal adenocarcinoma. Our lab has developed a 3D organoid assay to display ADM using primary, human pancreatic acinar cells to study the rate of transdifferentiation among these three different races. Preliminary data shows that the rate of ADM is occurring significantly faster (p &amp;lt; 0.05) in Blacks/African Americans (White=11, Hispanic=10, Black/African American=5), which may explain the disproportionately behind the incidence and mortality rates for this race in pancreatic diseases. We additionally use nanoparticles to study the biomechanical properties (I.e., viscoelasticity, storage modulus) of the ADM microenvironment which shows a stiffer microenvironment in Blacks/African Americans than for the other races (White=4, Hispanic=4, Black/African American=1). Furthermore, I study the use of histone deacetylase (HDAC) inhibitors in reversing the process of ADM, which has consequently shown race-related outcomes, with Blacks/African Americans displaying a significant chemoresistance (p &amp;lt; 0.05) to HDAC treatment (White=6, Hispanic=6, Black/AA=3) by utilizing an ADM reversal index (ADMRI). Through further analysis, the plan is to continue procuring human samples from these three races to isolate an ADM-specific biomarker in relation race and drug reversal by studying the expression/activity of pancreatic associated genes by bulk-RNA and single-cell sequencing. Citation Format: Corey Perkins, Jinmai Jiang, Hesam Hakimjavadi, David Quashie Jr, Yating Mao, Jamel Ali, Thomas D. Schmittgen. Race plays a role on the rate of transdifferentiation in human pancreatic acinar ductal metaplasia and its' drug response [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR003.
Abstract B082: Autoimmune conditions and pancreatic cancer risk in older American adults
Authors: Fancheng Yuan, Ruth M. Pfeiffer, Sachelly Julian-Serrano, Simran Arjani, Michael J. Barrett, Jill Koshiol, Rachael Z. Stolzenberg-Solomon
Journal: Cancer Research (2022)

Abstract Pancreatic cancer (PC) is highly fatal, and its incidence is increasing in the United States. Population-based registry studies suggest associations between a few autoimmune conditions and PC risk, albeit based on a relatively small number of cases. We hypothesize that autoimmune conditions are associated with risk of PC. We conducted a population-based, nested case-control study to examine the association between autoimmune conditions and PC risk within the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare population. Incident primary malignant PC cases (n=80,074) were adults &amp;gt; 66 years and diagnosed between 1992 and 2015. Controls (n=320,296) were alive at the time cases were diagnosed and frequency-matched to cases (4:1 ratio) by age, sex, and year of diagnosis. We used multivariable-adjusted, unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 45 autoimmune conditions identified from Medicare claims. Eight autoimmune conditions including ankylosing spondylitis (OR = 1.45; 95% CI: 1.14-1.84), Graves’ disease (OR = 1.18; 95% CI: 1.03-1.34), localized scleroderma (OR = 1.27; 95% CI: 1.06-1.52), pernicious anemia (OR = 1.08; 95% CI: 1.02-1.14), primary sclerosing cholangitis (OR = 1.37; 95% CI: 1.18-1.59), pure red cell aplasia (OR = 1.31; 95% CI: 1.16-1.47), type 1 diabetes (OR = 1.11; 95% CI: 1.07-1.15), and ulcerative colitis (OR = 1.18; 95% CI: 1.07-1.31) were associated with increased PC risk (false discovery rate-adjusted P values &amp;lt; 0.10). In subtype analyses, these conditions were associated with pancreatic ductal adenocarcinoma, whereas only ulcerative colitis was associated with pancreatic neuroendocrine tumors. Our results support the hypothesis that autoimmune conditions may play a role in PC development. Citation Format: Fancheng Yuan, Ruth M. Pfeiffer, Sachelly Julian-Serrano, Simran Arjani, Michael J. Barrett, Jill Koshiol, Rachael Z. Stolzenberg-Solomon. Autoimmune conditions and pancreatic cancer risk in older American adults [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B082.
Abstract B073: C-terminal Binding Protein (CtBP): a critical regulator of ErbB2/3 signaling in PDAC
Authors: Kranthi Kumar Chougoni, Haemin Park, Priyadarshan K. Damle, Martin Michael Dcona, Barbara Szomju, Mikhail G. Dozmorov, Michael Idowu, Steven R. Grossman
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal of human cancers with a 5-year survival of ~10%, underscoring the need to identify new therapeutic vulnerabilities. Previously, we reported high expression of transcriptional co-regulators C-terminal binding proteins (CtBP) 1 and 2 in human PDAC, however their precise role in PDAC formation or progression remains unclear. Here we have studied PDAC tumor dependency on CtBPs for growth and metastasis, using an orthotopic syngeneic pancreatic tumor mouse model employing a mouse PDAC cell line (CKP) derived from a pancreatic tumor that formed in a mouse expressing mutated K-Ras in the setting of p53 deletion. CRISPR-based homozygous deletion of Ctbp2 in the parental mouse PDAC cell line (CKP CtBP2 KO) dramatically decreased orthotopic PDAC tumor growth, drastically reduced metastatic potential, and significantly prolonged survival. Interrogating differential gene expression of the orthotopic PDAC tumors from Ctbp2 WT vs Ctbp2 KO cohorts, we identified significant downregulation of the EGFR-superfamily receptor ErbB3 in Ctbp2 KO tumors, and further determined that CtBP2 regulates expression of both the ErbB2 and 3 EGFR superfamily genes in PDAC cells. We therefore hypothesized that CtBP regulation of physiologic ErbB2/3 signaling contributes, in part, to PDAC growth and metastasis. Indeed, we observed that Ctbp2 KO cells exhibited near complete loss of ErbB2/3 expression and exhibited severely attenuated activation of phospho-Akt after neuregulin stimulation of ErbB2/3, and furthermore, human PDAC cells also demonstrated CtBP dependence of ErbB3 expression. Our results suggest that a subset of PDAC tumors are dependent on physiologic ErbB2/3 signaling and could be targeted by pharmacologic inhibitors of ErbB2 and/or ErbB3. Providing proof of concept, the ErbB2-targeted multikinase inhibitor lapatinib effectively killed the ErbB3 expressing CKP PDAC cells, while CKP CtBP2 KO cells, where ErbB3 expression was extinguished, were resistant to lapatinib. Taken together, our data suggests that ErB2/3 targeted therapeutics can effectively target a critical PDAC dependency on physiologic ErbB2/3 signaling which is the result of CtBP’s oncogenic transcriptional program that drives PDAC tumor progression. Citation Format: Kranthi Kumar Chougoni, Haemin Park, Priyadarshan K. Damle, Martin Michael Dcona, Barbara Szomju, Mikhail G. Dozmorov, Michael Idowu, Steven R. Grossman. C-terminal Binding Protein (CtBP): a critical regulator of ErbB2/3 signaling in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B073.
Abstract C069: Using a cancer-on-a-chip approach to study the pancreatic cancer tumor microenvironment
Authors: Samantha B. Kemp, Andrei Georgescu, Jason Pitarresi, Takeshi Katsuda, Il-Kyu Kim, Dora Racca, John Tobias, Dan Huh, Ben Stanger
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is overwhelmingly resistant to therapy. PDAC tumors are characterized by an immunosuppressive fibroinflammatory stroma and can be broadly classified into those with an abundance of T cells or a paucity of T cells. Our lab has previously identified several tumor cell intrinsic factors that regulate the degree of T cell infiltration and response to immunotherapy, but it remains unknown how these factors influence T cell trafficking through the vasculature to the tumor. We used in vivo models and a cancer-on-a-chip platform to examine immune-vascular crosstalk in the pancreatic tumor microenvironment (TME). We first sought to characterize the vascular landscape in PDAC. Following up from previous work in the lab, we used bulk RNA sequencing appraoches to identify a subset of hyper-vascular murine PDAC lines. Using an in vivo dextran assay, we determined that endothelial-high tumors have increased vascular perfusion. We next utilized an in vitro tube formation assay to assess if the defects seen in tumor vasculature are from tumor-cell derived factors. Endothelial cells cultured in conditioned media from endothelial-low tumors had defects in tubule formation. We further identified endothelial-low tumors have a defect in pericyte coverage of the vessel. We next utilized organ-on-a-chip devices to assess angiogenesis in PDAC. Endothelial cells and fibroblasts self-assemble into a 3D vascular network when incorporated into the microdevices. In the absence of tumor cells, mature vascular networks formed on day 4 of culture. Interestingly, vascular networks formed faster in the presence of PDAC tumor cells, suggesting a tumor derived factor enhanced angiogenesis. The cancer-on-a-chip devices are perfusable and allow for the incorporation of other TME components. Future directions, include incorporation of myeloid cells and perfusing fluorescently labeled T cells into the vascular networks and using live imaging to monitor T cell trafficking in different PDAC TME settings. Further, we will use immune checkpoint blockade and CAR T cells to identify methods to enhance tumoral T cell infiltration. Citation Format: Samantha B. Kemp, Andrei Georgescu, Jason Pitarresi, Takeshi Katsuda, Il-Kyu Kim, Dora Racca, John Tobias, Dan Huh, Ben Stanger. Using a cancer-on-a-chip approach to study the pancreatic cancer tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C069.
Abstract A039: Beta-sheet richness of extracellular vesicles for pancreatic cancer screening
Authors: Komila Rasuleva, Dali Sun
Journal: Cancer Research (2022)

Abstract Pancreatic cancer patients predominantly present with advanced disease at the time of diagnosis, which is the reason for its high mortality. A noninvasive fast-screening method to detect asymptomatic early-stage disease is an unmet need. Tumor-derived extracellular vesicles (EVs) bearing information from parental cells were believed to be a good candidate for noninvasive diagnosis biomarkers. Many pancreatic cancer diagnostic assays use only a single cancer-associated marker/signature, which are either subtype-specific or could be easily masked by high background signals. The purpose of this research is to develop a fast method of noninvasive diagnosis biomarkers for pancreatic cancer screening as collective attribute by analyzing the secondary structure of the EV proteins using circular dichroism (CD), Fourier transform infrared (FT-IR), and fluorescent staining. We developed a high-throughput noninvasive assay by using the β-sheet richness (BR) of the tumor-derived EVs as a target in order to recognize EVs originating from malignant and nonmalignant cells. Extracellular vesicles bearing information from parental cells, play important roles in cell−cell signaling, immune response, and metastasis. We were able to indicate that pancreatic cancer EV proteins were more β-sheet-rich than their healthy counterparts. A fast method assay was developed that combines immunoprecipitation (IP) and Thioflavin T (ThT) fluorescent dye, termed as EvIPThT, that binds directly to β-sheet-rich proteins into EVs. This assay readout of a review pilot companion showed adequate biased power contrasting samples from cancer cases, disease controls and healthy controls. This method appeared to be the simple, inexpensive, low sample, less time consuming, high-throughput, and automatable, since no β-sheet richness change was observed in the treated and nontreated cells, EvIPThT assay shows promising results as a pancreatic cancer screening assay, filling the translational gaps left by current EV detection methods. Citation Format: Komila Rasuleva, Dali Sun. Beta-sheet richness of extracellular vesicles for pancreatic cancer screening [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A039.
Abstract B007: Enhancing autophagy inhibition as a therapeutic strategy for pancreatic cancer
Authors: Jonathan M. DeLiberty, Ryan Robb, Claire E. Gates, Noah L. Pieper, Runying Yang, Clint A. Stalnecker, Kirsten L. Bryant
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth. We determined the role of mutationally activated KRAS, found in ~95% of PDAC, in supporting autophagy. Surprisingly, acute KRAS suppression was associated with increased autophagic flux. Pharmacologic inhibition of ERK MAPK phenocopied the genetic silencing of KRAS and increased autophagic flux. We speculated that the loss of ERK-driven metabolic processes may induce compensatory mechanisms to increase autophagy. We then addressed whether ERK inhibition increased PDAC dependence on autophagy. Supporting this possibility, we found that cotreatment with the autophagy inhibitor chloroquine (CQ) synergistically enhanced ERK inhibitor-mediated anti-proliferative activity. Our findings, together with similar observations by others, provided the rationale for our initiation of Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT04132505) or ERKi (LY3214996; NCT04386057) with hydroxychloroquine (HCQ) in PDAC. Our ongoing studies are centered on developing additional combinations for targeting autophagy. First, we performed a CRISPR/Cas-9 mediated genetic loss-of-function screen in the presence of CQ to determine additional sensitizers as well as mediators of resistance to autophagy inhibition. Top sensitizers included multiple facilitators of the DNA damage response, mTOR pathway components, and genes involved in the upstream regulation of the autophagy pathway. Second, we determined that autophagic signaling is temporally regulated following RAS pathway inhibition and hypothesize that further dissection of this regulation will improve current anti-nutrient scavenging treatment strategies. We conclude that concurrent suppression of multiple metabolic processes, to block compensatory rebound activities, will be needed for effective PDAC treatment. Citation Format: Jonathan M. DeLiberty, Ryan Robb, Claire E. Gates, Noah L. Pieper, Runying Yang, Clint A. Stalnecker, Kirsten L. Bryant. Enhancing autophagy inhibition as a therapeutic strategy for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B007.
Abstract A015: Rationale for the use of pulsed rather than continual dosing of the novel Focal Adhesion Kinase inhibitor AMP945 in pancreatic cancer
Authors: John Lambert, Mark Devine, Anthony Bishop
Journal: Cancer Research (2022)

Abstract Amplia Therapeutics Limited is developing AMP945, a highly selective inhibitor of Focal adhesion kinase (FAK) for the treatment of pancreatic cancer in combination with standard of care gemcitabine and nab-paclitaxel.1 FAK has been associated with the activity of myofibroblasts and collagen deposition and remodeling in PDAC. In preclinical studies, AMP945 displays potent anti-fibrotic activity in vitro and in vivo. In mouse models of PDAC, pulsed dosing of AMP945 added to gemcitabine and nab-paclitaxel inhibited collagen deposition and cross-linking and potentiated the effect of chemotherapy leading to increased survival.2A Phase 1 trial of AMP945 has been completed in which AMP945 showed excellent safety, tolerability, and pharmacokinetic properties as well as pharmacodynamic evidence of target engagement. Amplia’s recently initiated Phase 1b/2a clinical trial AMP945-PC-2013 (ACCENT) will assess a pulse dosing regimen of AMP945 in combination with gemcitabine and nab-paclitaxel as first-line therapy in patients with advanced pancreatic cancer. In ACCENT, patients will undergo a one-week oral loading dose of AMP945 and will be pulse dosed for four days prior to IV administration of gemcitabine and nab-paclitaxel, given according to a standard treatment schedule. Once daily oral dosing has anticipated benefits in terms of limitation of risk of acquired resistance, minimal potential for drug-drug interactions, adherence to therapy, and allows patients to self-administer AMP945 with the aim of potentiating response to standard of care chemotherapy. This abstract presentation will report on AMP945’s development status and the clinical rationale and status of the ACCENT trial. 1. Von Hoff et al., N Engl J Med 2013; 369:1691-1703 2. Murphy KJ et al. Sci Adv. 2021 Oct;7(40):eabh0363. 3. https://clinicaltrials.gov/ct2/show/NCT05355298 Citation Format: John Lambert, Mark Devine, Anthony Bishop. Rationale for the use of pulsed rather than continual dosing of the novel Focal Adhesion Kinase inhibitor AMP945 in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A015.